Our aim is to understand at the molecular level the mechanism behind the lengthy lifespan of IgG, which is 4 to 20 times greater than the other Ig classes. An understanding of the mechanism by which IgG lifespan is regulated will enable its therapeutic manipulation in a unique manner both to enhance the protective effects of antibodies and to temper the harmful aspects of autoantibodies. The hypothesis describing the mechanism, originally proposed by Brambell in the 1960s and updated by recent findings, says that IgG is pinocytosed nonspecifically by many cells of the body into acidic vesicles where at low pH, it binds to an integral membrane protein with high affinity for IgG; namely, the neonatal Fc receptor (FcRn), which is a beta2-microglobulin associated MHC class I-like heterodimer. IgG thus complexed with FcRn and saved from a degradative fate, is then trafficked in intracellular vesicles back to the plasma membrane where, at physiologic pH, it dissociates from the receptor and is free to recycle. Our recent findings have compelled us to modify this hypothesis in two ways. First, our anti-receptor antibodies localize FcRn not only to a cytoplasmic vesicular compartment but as well to the trans-Golgi network (TGN), which we propose, serves as a reservoir for trafficking FcRn. Second, we find abundant FcRn in cells of the extravascular space, such as epithelium, fibroblasts, macrophages, and some parenchyma, in addition to endothelium. Thus, while endothelium may be the accepted site of IgG degradation, the predominant site where IgG is protected from degradation is, we propose, in these cells of the extravascular space. Adaptively, it is here in the tissues at local sites of antibody action where IgG lifespan is longest. Our modified hypothesis presents a variety of predictions for us to test. We will determine precisely by several means where FcRn is expressed in the body and where it is localized at the subcellular level, colocalizing it with markers of various cellular compartments. We will determine the route IgG takes as it moves through a cell, being deflected from the degradative pathway by binding to FcRn. And we will test whether TGN serves as a reservoir for FcRn as it trafficks about the cell protecting IgG from a degradative fate. Our technical approaches to the various aims are broad-based and collaborative and include the methods of cellular and molecular biology, biochemistry, and immunology.